1. The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion
- Author
-
Erwan Goy, Maxime Tomezak, Caterina Facchin, Nathalie Martin, Emmanuel Bouchaert, Jerome Benoit, Clementine de Schutter, Joe Nassour, Laure Saas, Claire Drullion, Priscille M Brodin, Alexandre Vandeputte, Olivier Molendi-Coste, Laurent Pineau, Gautier Goormachtigh, Olivier Pluquet, Albin Pourtier, Fabrizio Cleri, Eric Lartigau, Nicolas Penel, Corinne Abbadie, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Oncovet Clinical Research [Loos] (Eurasanté - OCR), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP), Physique - IEMN (PHYSIQUE - IEMN), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, This work was supported by the Centre National de la Recherche Scientifique, the Université de Lille, the Ligue contre le Cancer (Comité du Pas-de-Calais, Comité de la Somme, Comité du Nord), the Cancéropole Nord-Ouest, the Institut Pasteur de Lille, the SIRIC OncoLille (Grant INCa-DGOS-Inserm 6041), the Agence Nationale de Recherche (ANR-10-EQPX-04-01), the Feder (12001407 [D-AL]), and the Contrat de Plan Etat Région CPER Cancer 2015-2020. EG had a fellowship from the Institut Pasteur de Lille and the Région Hauts-de-France. MT had a fellowship from the Université de Lille. CF had a fellowship from the European Erasmus program. JN had fellowships from the Université de Lille and from the Association pour la Recherche sur le Cancer. LS and CD had fellowships from the Région Hauts-de-France. We thank Thomas Lacornerie for giving access to the Varian CLINAC and for performing dose profiles. We thank the Bioimaging Center Lille-Nord de France (Campus Calmette), especially Antonino Bongiovanni and Hélène Bauderlique, for imaging and cytometry facilities. We thank the PLETHA animal facility, especially Thierry Chassat and David Hannebique. We thank David Dombrowicz for giving access to the BD Influx (Becton Dickinson). We thank Benoit Vatrinet, Anaïs Engrand, and Olivier Samyn for technical help. The authors have no conflicting financial interests., FundingLigue Contre le CancerCorinne AbbadieSIRIC Oncolille (INCa-DGOS-Inserm 6041)Corinne AbbadieAgence Nationale de la Recherche (ANR-10-EQPX-04-01)Priscille M BrodinFeder (12001407 (D-AL))Priscille M BrodinInstitut Pasteur de Lille, France (PhD student Fellowship)Erwan GoyRegion des Hauts-de-France, France (PhD student Fellowship)Erwan GoyEuropean Erasmus Program (Graduate student Fellowship)Caterina FacchinFondation ARC pour la Recherche sur le Cancer (PhD student Fellowship)Joe NassourRegion des Hauts-de-France (Engineer Fellowship)Laure SaasRegion des Hauts-de-France (Post-doctoral Fellowship)Claire Drullion, and CLERI, FABRIZIO
- Subjects
DNA Repair ,General Immunology and Microbiology ,Carcinogenesis ,General Neuroscience ,Neoplasms, Second Primary ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,General Medicine ,[SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,General Biochemistry, Genetics and Molecular Biology ,[SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,Mice ,Cell Transformation, Neoplastic ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Animals ,DNA Breaks, Single-Stranded ,Cellular Senescence ,DNA Damage - Abstract
International audience; A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient’s treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.
- Published
- 2022